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NIHR Signal Oral ibuprofen may be an option for closing patent ductus arteriosus in premature babies

A high dose of oral ibuprofen was more likely to close a patent ductus arteriosus in premature babies when compared with standard doses of intravenous ibuprofen or indometacin.

Before birth, a baby's lungs aren't needed for breathing. Most blood bypasses the lungs through a large vessel called the ductus arteriosus directly from the pulmonary artery into the aorta to supply the main circulation. Once born, blood flows through the lungs, and the ductus arteriosus usually closes in the first few days. If it doesn't close it is referred to as "patent". This condition is much more common in premature babies and doesn't always need treatment, but if causing problems may be managed by restriction of fluids, drug therapy, or surgery.

This systematic review and network meta-analysis suggests that a higher dose of ibuprofen given orally is an option worth considering for closing a persistent patent ductus arteriosus. There appear to be few serious adverse effects except in extremely low birth weight infants. This may reduce the need for surgery in larger infants.

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Why was this study needed?

Patent ductus arteriosus affects around 5 in every 100,000 babies. It is common in extremely premature infants and occurs in about 65% of infants born at less than 28 weeks.

There are a number of treatment options, which include surgery or drugs to close a persistent patent ductus arteriosus. Conservative management is also an option, where clinicians wait to see if the patent ductus arteriosus closes on its own within an infant’s first few days. There has been little evidence to base decisions on. This has led to the use of different drugs, in different doses and different methods of administration.

This study aimed to summarise the evidence on which drug treatments are the best choice.

What did this study do?

This systematic review included 68 randomised clinical trials with 4,802 premature infants (born before 37 weeks gestation). The data from these trials was synthesised using network meta-analyses.

Fourteen different variations of indometacin, ibuprofen or acetaminophen were used in the studies. These variations included different routes of administration (intravenous or oral), doses (standard dose, high dose or prolonged course), method of administration (bolus dose or continuous infusion), and included other interventions carried out at the same time. Some trials compared drugs, doses or routes of administration against others, and some compared drugs with placebo or no treatment.

Preterm infants treated were over 30 weeks gestation, and many trials were published in the 1980’s and 90’s. This means that the conclusions may only cautiously apply to modern intensive care and children at younger gestational age.

What did it find?

Patent ductus arteriosus closed within one week of all interventions in 67.4% (2,867 of 4,256) infants (in 60 studies).

A high dose of oral ibuprofen was associated with a greater chance of patent ductus arteriosus closure than a standard dose of intravenous ibuprofen (odds ratio [OR] 3.59, 95% credible interval [CI] 1.64 to 8.17). This is equivalent to about 199 (95% CI 95 to 258) more closures among 1,000 infants treated. A high dose of ibuprofen was defined as 15-20mg/kg followed by 7.5-10mg/kg every 12 to 24 hours for a total of three. A standard dose was defined as 10mg/kg followed by 5mg/kg every 12 to 24 hours for a total of three doses.

A high dose of oral ibuprofen was also associated with a greater chance of patent ductus arteriosus closure than a standard dose of intravenous indometacin (OR 2.35, 95% CI 1.08 to 5.31. Equivalent to about 124 (95% CI 14 to 188) more closures among 1,000 infants treated. A standard dose of for intravenous indometacin was defined as 0.1 to 0.3mg/kg every 12 to 24 hours for a total of three doses.

Infant mortality was reported in 46 studies with 3,329 infants. The incidence of death was 11.9% in all studies, and 17.4 % in the placebo or no treatment groups. In the network meta-analysis, a standard dose of oral ibuprofen ranked best preventing death, but there was no statistically significant difference between any of the treatment options neonatal mortality.

In these studies, a high dose of oral ibuprofen was not associated with an increased incidence of enterocolitis (a bowel condition found in premature babies).

What does current guidance say on this issue?

NICE published interventional procedures guidance in 2004 on closing the duct using endovascular techniques, compared with open surgery. Local NHS protocols suggest using indometacin or ibuprofen if the duct doesn’t close on its own, with surgery an option if the drugs don’t work.

What are the implications?

A high dose of oral ibuprofen appears to give the highest chance of patent ductus arteriosus closure in premature babies.

Concerns remain about the use of nonsteroidal anti-inflammatory drugs such as oral ibuprofen due to concerns about necrotising enterocolitis, but this study found no association in older children.

There may be other considerations in clinical practice, such as the weight of the baby or other illnesses, and the conclusions of this study need to be considered in the context of current practice within the UK.

Why was this study needed?

Patent ductus arteriosus affects around 5 in every 100,000 babies. It is common in extremely premature infants and occurs in about 65% of infants born at less than 28 weeks.

There are a number of treatment options, which include surgery or drugs to close a persistent patent ductus arteriosus. Conservative management is also an option, where clinicians wait to see if the patent ductus arteriosus closes on its own within an infant’s first few days. There has been little evidence to base decisions on. This has led to the use of different drugs, in different doses and different methods of administration.

This study aimed to summarise the evidence on which drug treatments are the best choice.

What did this study do?

This systematic review included 68 randomised clinical trials with 4,802 premature infants (born before 37 weeks gestation). The data from these trials was synthesised using network meta-analyses.

Fourteen different variations of indometacin, ibuprofen or acetaminophen were used in the studies. These variations included different routes of administration (intravenous or oral), doses (standard dose, high dose or prolonged course), method of administration (bolus dose or continuous infusion), and included other interventions carried out at the same time. Some trials compared drugs, doses or routes of administration against others, and some compared drugs with placebo or no treatment.

Preterm infants treated were over 30 weeks gestation, and many trials were published in the 1980’s and 90’s. This means that the conclusions may only cautiously apply to modern intensive care and children at younger gestational age.

What did it find?

Patent ductus arteriosus closed within one week of all interventions in 67.4% (2,867 of 4,256) infants (in 60 studies).

A high dose of oral ibuprofen was associated with a greater chance of patent ductus arteriosus closure than a standard dose of intravenous ibuprofen (odds ratio [OR] 3.59, 95% credible interval [CI] 1.64 to 8.17). This is equivalent to about 199 (95% CI 95 to 258) more closures among 1,000 infants treated. A high dose of ibuprofen was defined as 15-20mg/kg followed by 7.5-10mg/kg every 12 to 24 hours for a total of three. A standard dose was defined as 10mg/kg followed by 5mg/kg every 12 to 24 hours for a total of three doses.

A high dose of oral ibuprofen was also associated with a greater chance of patent ductus arteriosus closure than a standard dose of intravenous indometacin (OR 2.35, 95% CI 1.08 to 5.31. Equivalent to about 124 (95% CI 14 to 188) more closures among 1,000 infants treated. A standard dose of for intravenous indometacin was defined as 0.1 to 0.3mg/kg every 12 to 24 hours for a total of three doses.

Infant mortality was reported in 46 studies with 3,329 infants. The incidence of death was 11.9% in all studies, and 17.4 % in the placebo or no treatment groups. In the network meta-analysis, a standard dose of oral ibuprofen ranked best preventing death, but there was no statistically significant difference between any of the treatment options neonatal mortality.

In these studies, a high dose of oral ibuprofen was not associated with an increased incidence of enterocolitis (a bowel condition found in premature babies).

What does current guidance say on this issue?

NICE published interventional procedures guidance in 2004 on closing the duct using endovascular techniques, compared with open surgery. Local NHS protocols suggest using indometacin or ibuprofen if the duct doesn’t close on its own, with surgery an option if the drugs don’t work.

What are the implications?

A high dose of oral ibuprofen appears to give the highest chance of patent ductus arteriosus closure in premature babies.

Concerns remain about the use of nonsteroidal anti-inflammatory drugs such as oral ibuprofen due to concerns about necrotising enterocolitis, but this study found no association in older children.

There may be other considerations in clinical practice, such as the weight of the baby or other illnesses, and the conclusions of this study need to be considered in the context of current practice within the UK.

Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis

Importance: Despite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to treat those developing a hemodynamically significant PDA.
Objectives: To estimate the relative likelihood of hemodynamically significant PDA closure with common pharmacotherapeutic interventions and to compare adverse event rates. Data Sources and Study Selection: The databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen vs each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA. Data Extraction and Synthesis: Data were independently extracted in pairs by 6 reviewers and synthesized with Bayesian random-effects network meta-analyses. Main Outcomes and Measures: Primary outcome: hemodynamically significant PDA closure; secondary: included surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage.
Results: In 68 randomized clinical trials of 4802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2867 of 4256 infants).
A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199 [95% CrI, 95-258] more per 1000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08-5.31]; absolute risk difference, 124 [95% CrI, 14-188] more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. Conclusions and Relevance: A high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure vs standard doses of intravenous ibuprofen or intravenous indomethacin; placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage. Trial Registration: PROSPERO Identifier: CRD42015015797.

Expert commentary

The authors have concluded that a high dose of oral ibuprofen is the most effective medical intervention to close the persistent patent ductus arteriosus.

They recognise the limitations of giving oral ibuprofen or paracetamol in extremely low birth weight infants under 28 weeks of gestation, especially in first few days after birth because of the risk of necrotising enterocolitis.

Oral high dose ibuprofen or paracetamol could be a viable option to treat patent ductus arteriosus in more mature infants (at 30 weeks of gestation or more). However, more evidence is required on its safety and efficacy in extremely low birth weight infants before it could be recommended as the first-line option.